1. Field of the Invention
The invention relates to substituted 1- and 2-naphthol Mannich bases, processes for their preparation, medicaments comprising these compounds and the use of these compounds for the preparation of medicaments.
2. Description of the Background
Pain is one of the basic clinical symptoms. There is a worldwide need for effective pain treatments. The urgent need for action for target-orientated treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood successful and satisfactory pain treatment for the patient, is documented in the large number of scientific works which have been published in the field of applied analgesia and basic research in nociception in recent years.
Conventional opioids, such as e.g. morphine, are effective in the treatment of severe to very severe pain. However, they have as undesirable concomitant symptoms, inter alia, respiratory depression, vomiting, sedation, constipation and development of tolerance.
Tramadol hydrochloride-(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanolxe2x80x94occupies a special position among analgesics having an action on the central nervous system, since this active compound brings about potent inhibition of pain without the side effects known of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)). Research is being conducted worldwide into further pain-inhibiting agents.
The object of the present invention was therefore to provide new compounds which are suitable in particular as active compounds in medicaments.
These active compounds should be suitable in particular for pain treatment and for treatment of inflammatory and allergic reactions, drug and/or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, states of shock, migraines, narcolepsy, excess weight, asthma, glaucoma and/or hyperkinetic syndrome.
This object is achieved according to the invention by providing substituted 1- and 2-naphthol Mannich bases of the following general formula I which have a pronounced analgesic action and which moreover are suitable for treatment of/combating inflammatory and allergic reactions, drug and/or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, states of shock, migraines, narcolepsy, excess weight, asthma, glaucoma and/or hyperkinetic syndrome.
The invention therefore provides substituted 1- and 2-naphthol Mannich bases of the general formula I 
wherein
R1=CH(R9)N(R10)(R11) and R2=OR12 or
R1=OR12 and R2=CH(R9)N(R10)(R11),
and in each case the radicals
R3 to R8 are identical or different and=H, F, Cl, Br, CF3, CN, NO2, SO2NH2, SO2NHR13, NHR13, SR15, OR16, CO(OR20), CH2CO(OR21), CO(R22), a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably=H, F, Cl, Br, SO2NH2, NHR13, CO(R22), OR16, CO(OR20), a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, particularly preferably H, NHR13, CO(R22), OR16 or CO(OR20),
R9 denotes an aryl radical, a heteroaryl radical or an alkyl radical without an acid proton in the xcex1-position, preferably an unsubstituted phenyl radical or a phenyl radical which is at least monosubstituted by C1-4-alkyl, C1-3-alkoxy, halogen, CF3, CN, O-phenyl or OH, particularly preferably an unsubstituted phenyl radical or a 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-tert-butyl-phenyl, 3-tert-butyl-phenyl, 4-tert-butyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 5-bromo-2-fluoro-phenyl, 2-chloro-4-fluoro-phenyl, 2-chloro-5-fluoro-phenyl, 2-chloro-6-fluoro-phenyl, 4-bromo-2-fluoro-phenyl, 3-bromo-4-fluoro-phenyl, 3-bromo-2-fluoro-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichlorophenyl, 3,4-dichloro-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethylphenyl, 2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 2,5-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl radical, very particularly preferably an unsubstituted phenyl radical,
R10, R11 are identical or different and denote a branched or unbranched, saturated or unsaturated, unsubstituted or at least monosubstituted C1-6-alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl or phenethyl radical, preferably a saturated, unsubstituted or at least monosubstituted C1-6-alkyl radical, particularly preferably a CH3 radical,
or R10 and R11 together denote (CH2)n, where n=an integer from 3 to 6, or (CH2)2O(CH2)2, preferably (CH2)n, where n=4 or 5,
R12=H, COR22, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably=H, a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group,
R13=H, COR14, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably=H, a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, particularly preferably=H,
R14=H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group,
R15=H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group,
R16=H, CO(R17), a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably H, a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or CO(R17), particularly preferably H or CO(R17),
R17=H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy,
R18=H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or a phenyl or naphthyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy,
R20=H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably H, a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably H or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy,
R21=H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably=H, a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group,
R22=H, NHNH2, NHR18, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably H, a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group, NHNH2, NHR18 or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably NHNH2, NHR18 or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, very particularly preferably NHNH2 or NHR18,
and/or their racemates, enantiomers, diastereomers and/or corresponding bases and/or corresponding salts of physiologically tolerated acids,
excluding
the racemates of the compounds in which the radicals R1=CH(R9)N(R10)(R11) and R2=OR12 and in each case
the radicals R3 to R8 and R12=H, the radical R9=phenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 2-bromophenyl, benzo-1,3-dioxole, 4-CH3OCO-phenyl or 2-methoxyphenyl and the radicals R10 and R11 together=(CH2)5 or,
the radicals R3 to R8 and R12=H, the radical R9=phenyl, 4-methoxyphenyl, 4-dimethylaminophenyl, 4-hydroxy-2,3-di-tert-butylphenyl, 2,3-dihydrobenzodioxane, 4-nitrophenyl or benzo-1,3-dioxole and the radicals R10 and R11 together=(CH2)2O(CH2)2 or
the radicals R3 to R8 and R12=H, the radical R9=4-methoxyphenyl and the radicals R10 and R11 together=(CH2)4 or
the radical R3=CO(OR20), the radicals R4 to R8 and R12=H, the radical R9=phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl or p-benzaldehyde, the radicals R10 and R11 together=(CH2)5 and the radical R20=CH3 or
the radicals R3 to R8 and R12=H, the radical R9=phenyl and the two radicals R10 and R11 each=CH3, C2H5 or n-C3H7 or
the radicals R3 to R8 and R12=H, the radical R9=4-methoxyphenyl or benzo-1,3-dioxole and the radicals R10 and R11 each=CH3 or
the radicals R3 to R5, R7, R8, R12=H, the radical R6=Br, the radical R9=phenyl and the radicals R10 and R11 together=(CH2)5 or
the radicals R3 to R5, R7, R8, R12=H, the radical R6=Br, the radical R9=4-hydroxy-3,5-di-tert-butylphenyl and the radicals R10 and R11 together (CH2)2O(CH2)2 or
the radicals R3 to R8 and R12=H, the radical R9=phenyl and the radicals R10 and R11 each=CH3 as the hydrochloride or
the radicals R3 to R8 and R12=H, the radical R9=phenyl or 4-methoxyphenyl and the radicals R10 and R11 together=(CH2)5 as the hydrochloride or
the radical R3=CO(OR20), the radicals R4 to R8 and R12=H, the radical R9=phenyl, the radicals R10 and R11 together=(CH2)5 and the radical R20=CH3 as the hydrochloride or
the radicals R3 to R8 and R12=H, the radical R9=thiophene and the radicals R10 and R11 together=(CH2)2O(CH2)2 or
the radicals R3 to R8=H, the radical R12=CH3, the radical R9=thiophene, 4-methoxyphenyl or 3,4-dimethoxyphenyl and the radicals R10 and R11 together=(CH2)2O(CH2)2 
and the enantiomers of the compound of the general formula I in which R1=CH(R9)N(R10)(R11) and R2=OR12 and the radicals R3 to R8, R12=H, R9=phenyl and R10 and R11 together=(CH2)5 and
the racemates of the compounds in which the radicals R1=OR12 and R2=CH(R9)N(R10)(R11) and in each case the radicals
R3 to R8 and R12=H, the radical R9=phenyl, 2-bromophenyl, 3-bromophenyl or 4-bromophenyl and the radicals R10 and R11 together=(CH2)5 or
R3 to R8 and R12=H, the radical R9=phenyl or 2-nitrophenyl and the radicals R10 and R11 together=(CH2)2O(CH2)2 or
R3, R4, R6, R8 and R12=H, the radicals R5, R7=CH3, the radical R9=phenyl or 4-methoxyphenyl and the radicals R10 and R11 together=(CH2)5 or
R3 to R6, R8, R12=H, the radical R7=CH3, the radical R9=4-methoxyphenyl or phenyl and the radicals R10, R11 together=(CH2)5 or
R3 to R8 and R12=H, the radical R9=phenyl, the radical R10=CH3 and the radical R11=C6H11 or the radicals R10 and R11 each=CH3 or
R3 to R6, R8, R12=H, the radical R7=CH3, the radical R9=phenyl or 4-methoxyphenyl and the radicals R10 and R11 together=(CH2)2O(CH2)2 or
R3, R4, R6, R8, R12=H, the radicals R5 and R7=CH3, the radical R9=4-methoxyphenyl and the radicals R10 and R11 together=(CH2)2O(CH2)2 or
R3 to R8, R12=H, the radical R9=phenyl and the radicals R10 and R11 together=(CH2)2O(CH2)2 as the hydrochloride.